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Metabolic adaptation in residual triple negative breast cancer following chemotherapy

化疗后残留三阴性乳腺癌的代谢适应

基本信息

批准号：
10585688
负责人：
Gloria Vittone Echeverria
金额：
$ 44.43万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-27 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585688
关键词：
3-Dimensional Address Adjuvant Chemotherapy Adjuvant Therapy Anthracycline Automobile Driving Biopsy Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Cancer Patient Carbon Cell Cycle Cells Cessation of life Chemoresistance Data Disease Equilibrium Face Generations Genetic Goals Guanosine Triphosphate Phosphohydrolases Human Immune system Immunocompetent In Vitro Life Machine Learning Maintenance Malignant Neoplasms Mathematics Measures Mediating Medical Oncology Metabolic Metabolism Mitochondria Mus Neoadjuvant Therapy Oncogenic Optic atrophy 1 Organelles Organoids Oxidative Phosphorylation Patient-Focused Outcomes Patients Phenotype Platinum Play Population Process Protein Dynamics Proteins Recurrence Refractory Regulation Residual Neoplasm Residual state Role Scanning Electron Microscopy Signal Pathway Structure Testing Therapeutic Tissue imaging Transmission Electron Microscopy Transplantation Tumor Burden Visualization chemotherapy high risk improved in vivo inhibitor insight knock-down malignant breast neoplasm mitochondrial genome mitochondrial metabolism mouse model mutant neoplastic cell novel patient derived xenograft model pharmacologic preference response targeted treatment taxane therapeutic target therapy resistant transcriptomics treatment response triple-negative invasive breast carcinoma tumor tumor-immune system interactions tumorigenic

项目摘要

ABSTRACT Oxidative phosphorylation (oxphos), a mitochondrial energy generation process, promotes chemotherapeutic resistance in breast and other cancers. In fact, transplantation of mitochondria from tumorigenic cells into non- tumorigenic cells demonstrated these organelles are necessary and sufficient for aggressive phenotypes of triple negative breast cancer (TNBC) cells. Nearly 50% of TNBC patients treated with neoadjuvant (pre-surgical) chemotherapy (NACT; combined anthracyclines, platinums, and/or taxanes) will harbor substantial residual tumor burden, leading to extremely high risk of recurrence and death4. There are no approved targeted therapies for neoadjuvant treatment of non-BRCA-mutant TNBC. Thus, there is an urgent need to find ways to eradicate residual tumor cells. Furthermore, the mechanisms driving metabolic reprogramming in chemoresistant TNBC are unclear. Our comparisons of serial pre- and post-NACT patient-derived xenograft (PDX) and human TNBC biopsies revealed heightened oxphos signatures in residual tumor cells, and we demonstrated oxphos is a unique therapeutic vulnerability of residual TNBC. We observe significantly higher protein levels of the mitochondrial fusion-driving GTPase optic atrophy 1 (OPA1) in post- vs. pre-NACT TNBC biopsies. Furthermore, high expression of mitochondrial fusion-driving proteins in breast cancer is associated with poor survival. The impact of mitochondrial structure, dictated by the balance of mitochondrial fission and fusion, on metabolism varies highly across tumor types. Despite the importance of mitochondria to metabolism, no studies have addressed how mitochondrial structure impacts metabolic states driving TNBC therapeutic responses. Our preliminary data provide evidence that NACT increases mitochondrial fusion and metabolism in vitro and in vivo. We can increase oxphos and NACT resistance in TNBC cells by genetically or pharmacologically perturbing mitochondrial fission with Mdivi-1, a Drp1 inhibitor. Conversely, perturbation of mitochondrial fusion with MYLS22, an OPA1 inhibitor, decreased oxphos and NACT resistance. We hypothesize OPA1-driven mitochondrial fusion mediates an NACT-induced metabolic switch to promote chemoresistance in TNBC cells. To address this, our specific aims are to: 1) Determine if mitochondrial fusion is responsible for chemotherapy- induced oxphos in TNBC, and 2) Target and quantify mitochondrial fusion in residual TNBC mouse models and serial patient biopsies. These results will increase our mechanistic understanding of regulation of the mitochondrial life, as well as mechanisms driving metabolic adaptations in TNBC. Furthermore, our findings will provide additional metabolic therapeutic targets to overcome chemoresistance in residual TNBCs.

摘要